Umbilical cord blood (CB) is used to restore hematopoiesis in bone marrow transplant patients lacking sibling or unrelated donors. A major disadvantage of CB is the low cell dose with resultant delays in neutrophil engraftment and a high rate of engraftment failure. The major hypothesis of this grant is that CB progenitors expanded ex vivo prior to transplantation will provide more rapid neutrophil engraftment and less engraftment failure than unmanipulated CB. There are two populations that have been proposed to be responsible for rapid myeloid recovery: 1) mature progenitor cells, and 2) primitive hematopoietic stem cells. In this grant we will conduct three sequential phase II clinical trials to evaluate CB grafts expanded ex vivo to generate mature progenitors or primitive stem cells. The first trial, a continuation of the previous R01, will evaluate CB grafts in which committed CD34+ precursors have been selectively expanded. The second trial will evaluate CB grafts in which more primitive CB cells are expanded, using earlier-acting growth factors and novel technology described in the grant. Based upon the findings of these studies, the third trial will randomize patients to receive CB progenitors which are unmanipulated vs. expanded, using the expansion methodology in the first two trials that results in the fastest engraftment. We anticipate that infectious complications will be a major cause of morbidity and mortality in these trials. Although expanded CB may hasten neutrophil engraftment and reduce infections early posttransplant, it may not affect infections associated with delayed immune recovery. Delays in immune reconstitution in CB recipients are frequently reported. It is possible that the CB purification and expansion methods proposed in this grant, which result in selective loss of lymphoid cells, could further compromise immune reconstitution. Thus, we plan to comprehensively evaluate the immune reconstitution of CB recipients enrolled on the proposed trials. General immune function and CMV-specific immune reconstitution will be studied, because of the multiple, complimentary assays available and the expertise of the co-investigators who will be performing them. By randomizing patients in the third trial, we will be able to make an estimate of the relative efficacy of CB expansion technology as well as immune reconstitution in recipients of unmanipulated vs. expanded CB.